Brincidofovir Is Not a Substrate for the Human Organic Anion Transporter 1: A Mechanistic Explanation for the Lack of Nephrotoxicity Observed in Clinical Studies

Abstract

Background: Brincidofovir (BCV) is an orally bioavailable lipid conjugate of cidofovir (CDV) with increased in vitro potency relative to CDV against all 5 families of double-stranded DNA viruses that cause human disease. After intravenous (IV) administration of CDV, the organic anion transporter 1 (OAT1) transports CDV from the blood into the renal proximal tubule epithelial cells with resulting dose-limiting nephrotoxicity.

Objective: To study whether OAT1 transports BCV and to evaluate the pharmacokinetic and renal safety profile of oral BCV compared with IV CDV.

Methods: The cellular uptake of BCV and its major metabolites was assessed in vitro. Renal function at baseline and during and after treatment in subjects in BCV clinical studies was examined.

Results: In OAT1-expressing cells, uptake of BCV and its 2 major metabolites (CMX103 and CMX064) was the same as in mock-transfected control cells and was not inhibited by the OAT inhibitor probenecid. In human pharmacokinetic studies, BCV administration at therapeutic doses resulted in detection of CDV as a circulating metabolite; peak CDV plasma concentrations after oral BCV administration in humans were <1% of those observed after IV CDV administration at therapeutic doses. Analysis of renal function and adverse events from 3 BCV clinical studies in immunocompromised adult and pediatric subjects indicated little to no evidence of associated nephrotoxicity. Over 80% of subjects who switched from CDV or foscarnet to BCV experienced an improvement in renal function as measured by maximum on-treatment estimated glomerular filtration rate.

Conclusions: The lack of BCV uptake through OAT1, together with lower CDV concentrations after oral BCV compared with IV CDV administration, likely explains the superior renal safety profile observed in immunocompromised subjects receiving BCV compared with CDV.

Trial registration: ClinicalTrials.gov NCT01143181 NCT00942305 NCT01241344.

Conflict of interest statement

T. K. Tippin, M. E. Morrison, and T. M. Brundage are employees and shareholders of Chimerix. H. Momméja-Marin was formerly an employee of Chimerix.

Figures

FIGURE 1.

Chemical structures of BCV and metabolites.

FIGURE 2.

Net OAT1-mediated uptake of BCV, CDV, CMX103, and CMX064 in the absence or presence of probenecid. Net OAT1-mediated uptake was determined from total uptake in OAT1-expressing cells minus uptake in mock-transfected control cells after incubation with 5 μM BCV, 25 μM CDV, 25 μM CMX103, or 25 μM CMX064 for 5 minutes in the presence or absence of 100 μM probenecid. Data are mean and SD of triplicate or quadruplicate samples from one experiment. *P < 0.05 versus mock-transfected cells; †Significantly lower uptake in the presence of probenecid, a nonspecific inhibitor of OAT1.

FIGURE 3.

Mean change from BL in eGFR in virally infected subjects administered BCV (CMX001) or placebo (CMV Prevention Study). Mean change from BL in eGFR as calculated through the Modification of Diet in Renal Disease equation (4 inputs) is presented by visit and dose. P-values (Satterthwaite t test) for CMX001 100 mg BIW relative to pooled placebo: *Week 8, P = 0.0013 (CMX001 n = 31, placebo n = 36); †week 10, P = 0.0103 (CMX001 n = 21, placebo n = 21); ‡posttreatment week 1, P = 0.0025 (CMX001 n = 49, placebo n = 57).

FIGURE 4.

Percentages of subjects with stable or improved renal function based on CKD stage after multiple administrations of BCV (CMX001). eGFR was calculated for each subject and assigned to one of the 5 stages of CKD: stages 1 and 2, eGFR ≥60 mL·min−1·1.73 m−2; stage 3, 30–59 mL·min−1·1.73 m−2; and stages 4 and 5, ≤29 mL·min−1·1.73 m−2. Subjects were judged to have stable or improved renal function if the highest on-treatment CKD stage or last on-treatment CKD stage was the same as or lower than BL. Data are from the AdV Preemptive Treatment Study (Study 202 Pediatric) and the Expanded Access Study (Study 350 Pediatric, Study 350 Adult). Data from the Expanded Access Study are separated by dose for the adult subjects. wk, week.

FIGURE 5.

Percentages of subjects with improved eGFR from BL after multiple administrations of BCV in virally infected subjects with previous CDV use (Expanded Access Study). BL and on-treatment eGFR were estimated using the Modification of Diet in Renal Disease equation (4 inputs) formula in adult subjects and the Schwartz formula in pediatric subjects.